EP0101574B1 - 1-aminoalkyl-1,2,3,4-tétrahydro-beta-carbolines, leur préparation et leur utilisation comme médicaments - Google Patents

1-aminoalkyl-1,2,3,4-tétrahydro-beta-carbolines, leur préparation et leur utilisation comme médicaments Download PDF

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Publication number
EP0101574B1
EP0101574B1 EP83107370A EP83107370A EP0101574B1 EP 0101574 B1 EP0101574 B1 EP 0101574B1 EP 83107370 A EP83107370 A EP 83107370A EP 83107370 A EP83107370 A EP 83107370A EP 0101574 B1 EP0101574 B1 EP 0101574B1
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EP
European Patent Office
Prior art keywords
tetrahydro
acetyl
carboline
methyl
aminopropyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP83107370A
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German (de)
English (en)
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EP0101574A1 (fr
Inventor
Gerd Dr. Steiner
Claus D. Dr. Mueller
Dieter Dr. Lenke
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BASF SE
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BASF SE
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Priority to AT83107370T priority Critical patent/ATE25382T1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to 2-substituted 1- (aminoalkyl) -1,2,3,4-tetra-hydro-ß-carbolines, processes for their preparation and therapeutic agents containing them and their use in combating diseases.
  • R 1 is preferably hydrogen.
  • R 2 preferably hydrogen, methyl or ethyl and R 3 preferably C 2 -C 3 -acyl, in particular acetyl, n is preferably 3.
  • dialkylamino and monoalkylamino may be mentioned in particular - dialkylamino being preferred - and also the piperidine ring.
  • the reaction is conveniently carried out in the presence of a molar equivalent of a tertiary amine such as e.g. Triethylamine in an inert solvent such as a cyclic saturated ether, especially tetrahydrofuran or dioxane, or a polar aprotic solvent, preferably dimethylformamide, at temperatures from 0 to 150 ° C and is generally complete within 3 to 10 hours. It is also possible to work in the presence of an excess amount of the amino alcohol 111 used, which can serve simultaneously as a solvent and as an acid-binding agent.
  • a tertiary amine such as e.g. Triethylamine
  • an inert solvent such as a cyclic saturated ether, especially tetrahydrofuran or dioxane, or a polar aprotic solvent, preferably dimethylformamide
  • the free compounds of formula 1 are obtained in the form of crystals in the majority of cases and can be recrystallized by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol or a lower ester, preferably ethyl acetate, or purified by column chromatography.
  • a lower alcohol such as ethanol or a lower ester, preferably ethyl acetate
  • the compounds according to the invention obtained are converted into the acid addition salt of a physiologically tolerated acid.
  • suitable physiologically compatible organic or inorganic acids are: hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid and also oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid or benzene acid. Further acids can be found, for example, in J. Pharm. Sciences 66, (1977).
  • the acid addition salts are generally in a manner known per se by mixing the free base or its solutions with the corresponding acid or its solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol or propanol or a lower ketone such as acetone, methyl ethyl ketone or Methyl isobutyl ketone or an ether such as diethyl ether, tetrahydrofuran or dioxane.
  • a lower alcohol such as methanol, ethanol or propanol
  • a lower ketone such as acetone, methyl ethyl ketone or Methyl isobutyl ketone
  • an ether such as diethyl ether, tetrahydrofuran or dioxane.
  • R 2 represents an alkyl radical in the desired end product, this is obtained by reacting the N-2- Obtained acyl compound with alkyl chloride or dimethyl sulfate in an inert solvent.
  • the compounds 111 can be prepared by reacting the corresponding tryptamine derivatives with an ⁇ -haloaldehyde in a weakly acidic medium at 50 to 100 ° C.
  • the compounds according to the invention and their physiologically tolerated acid addition salts have valuable pharmacological properties. They have a strong antiarrhythmic effect and are therefore particularly suitable for the pharmacotherapy of cardiac arrhythmias.
  • the substances of male rats (strain: Sprague-Dawley, weight 200 to 250 g) are administered orally. 45 min later, the animals are anesthetized with thiobutabartial sodium (100 mg / kg i.p.). Aconitin serves as an arrhythmogenic substance, which i.v. 60 min after substance application. is infused (dosage rate: 0.005 mg / kg. min).
  • untreated animals N - 52
  • arrhythmias occur after 2.74 ⁇ 0.07 min on the ECG, the onset of which can be delayed by antiarrhythmics depending on the dose.
  • the dose is determined at which the first cardiotoxic symptoms (changes in the initial ECG) or neurotoxic symptoms (coordination disorders, convulsions, etc.) occur
  • the toxic doses and the antiarrhythmic doses (ED 50%) is a measure of the therapeutic breadth of the new compounds.
  • the well-known antiarrhythmic quinidine is used as a reference substance.
  • the compounds according to the invention are 3 to 59 times more effective than quinidine in aconitin arrhythmia (Example 4). In addition, they have a wider therapeutic range than quinidine.
  • the toxic doses are 12 times (Example 36) to 17 times (Example 22) larger than the antiarrhythmic ones, that of quinidine only 11 times.
  • the present invention therefore further relates to medicaments which contain a compound of the formula or their physiologically tolerable acid addition salt, and to the use of the new compounds in the treatment of diseases.
  • the new compounds can be used in the usual pharmaceutical application forms, solid or liquid, such as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories or solutions. These are manufactured in the usual way.
  • the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants and / or antioxidants (see H. Sucker et al: Pharmaceutical Technology, Thieme -Verlag, Stuttgart, 1978).
  • the administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 99% by weight.
  • the dosage of the compounds according to the invention depends on the age, condition and weight of the patient and on the type of application.
  • the daily dose of active ingredient is 5 to 75 mg / kg with oral and 1 to 10 mg / kg with parenteral administration.
  • E, (18 mM) 1- (3'-chloropropyl) -2-acetyl-9-methyl-1,2,3,4-tetrahydro-ß-carboline were in 150 ml of 40% dimethylamine solution in water suspended. transferred to a stirred autoclave and stirred at 150 ° C and autogenous pressure for 5 h. The mixture was then evaporated to dryness in vacuo, the light oil was dissolved in methylene chloride, water was added, the aqueous phase was adjusted to pH 10 with dilute sodium hydroxide solution and the aqueous phase was extracted twice more with methylene chloride.
  • the crude product was purified by column chromatography (silica gel, eluent methylene chloride / methanol 95/5) or by recrystallization from ethanol with the addition of activated carbon. 4.1 g (63%) were isolated, decomposition point - 80 ° C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (9)

1.1(aminoalkyle)-1,2,3,4-tétrahydro-β-carbolines substituées en 2, de formule 1
Figure imgb0013
dans laquelle
n est un nombre entier de 2 à 5
R1 represente un atome d'hydrogène ou d'halogène ou un reste trifluorométhyle, alkyle en C1-C4 ou alcoxy en C1-C4,
R2 un atome d'hydrogène ou un reste alkyle en C1-C3
R3 un reste acyle en C1-C3
R4 un reste alkyle ayant jusqu'à 4 atomes C, et
R5 un atome d'hydrogène ou un reste alkyle ayant jusqu'à 4 atomes C et
R4 et R5 ensemble avec l'atome N, aussi un cycle pipéridine qui peut être substitué par un ou plusieurs groupes alkyle en C1-3,

ainsi que leurs sels d'acides physiologiquement tolérables.
2.1 -[3'-(di-2-méthylpropyl)-aminopropyl]-2-acétyl-9-méthyl-1,2,3,4-tétrahydro-β-carboline.
3.1- (3'-dipropylaminopropyl)-2-acétyl-9-méthyl-1,2,3,4-tétrahydro-β-carboline.
4.1-(3,-isopropyl-propylaminopropyl)-2-acétyl-9-méthyl-1,2,3,4-tétrahydro-β-carboline.
5.1-[3'-(di-2-butyl)-aminopropyl]-2-acétyl-1,2,3,4-tétrahydro-β-carboline.
6.1-[3'-(di-n-butyl)-amlnopropyl]-2-acétyl-1,2,3,4-tétrahydro-β-carboline.
7. Médicament contenant un composé de formule 1 selon la revendication 1.
8. Composé de formule 1 selon la revendication 1, pour utilisation dans la lutte contre les maladies.
9. Procédé de préparation de composés de formule 1 selon la revendication 1, caractérisé par le fait que l'on fait réagir un composé de formule II
Figure imgb0014
dans laquelle n, R1, R2 et R3 ont les significations indiquées, avec une amine de formule
HNR4R5,

où R4 et R5 ont les significations indiquées et on transforme éventuellement les composés ainsi obtenus en sels d'acide physiologiquement tolerables.
EP83107370A 1982-08-05 1983-07-27 1-aminoalkyl-1,2,3,4-tétrahydro-beta-carbolines, leur préparation et leur utilisation comme médicaments Expired EP0101574B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT83107370T ATE25382T1 (de) 1982-08-05 1983-07-27 2-substituierte 1-aminoalkyl-1,2,3,4-tetrahydrobeta-carboline, ihre herstellung und verwendung als arzneimittel.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE3229214 1982-08-05
DE3229214 1982-08-05
DE19833309596 DE3309596A1 (de) 1982-08-05 1983-03-17 2-substituierte 1-(3'-aminoalkyl)-1,2,3,4-tetrahydro-ss-carboline, ihre herstellung und verwendung als arzneimittel
DE3309596 1983-03-17

Publications (2)

Publication Number Publication Date
EP0101574A1 EP0101574A1 (fr) 1984-02-29
EP0101574B1 true EP0101574B1 (fr) 1987-02-04

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Country Status (6)

Country Link
US (1) US4575508A (fr)
EP (1) EP0101574B1 (fr)
CA (1) CA1215367A (fr)
DE (2) DE3309596A1 (fr)
FI (1) FI832829A7 (fr)
HU (1) HU187958B (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3229215A1 (de) * 1982-08-05 1984-02-09 Basf Ag, 6700 Ludwigshafen 1-(halogenalkyl)-1,2,3,4-tetrahydro-ss-carboline, ihre herstellung und verwendung
US4663456A (en) * 1985-09-16 1987-05-05 American Home Products Corporation 2-(substituted piperazinylalkyl)β-carbolines useful in treatment of psychological disorders
DE3621413A1 (de) * 1986-06-26 1988-01-07 Boehringer Ingelheim Kg Verwendung carbocyclisch und heterocyclisch annelierter dihydropyridine als cardioprotektive mittel sowie neue heterocyclisch und carbocyclisch anellierte dihydropyridine, verfahren zu deren herstellung und zwischenstufen fuer deren herstellung
US4895853A (en) * 1986-12-18 1990-01-23 Harbor Branch Oceanographic Institution, Inc. Antitumor alkaloids
US4837325A (en) * 1987-02-26 1989-06-06 American Home Products Corporation Beta-carboline H1 -receptor antagonists
US4766124A (en) * 1987-02-26 1988-08-23 American Home Products Corporation Beta-carbolin H1-receptor antagonists
DE3827727A1 (de) * 1988-08-16 1990-02-22 Boehringer Ingelheim Kg Anellierte tetrahydropyridinessigsaeurederivate, verfahren zu deren herstellung und verwendung solcher verbindungen zur kardioprotektion
DE10252667A1 (de) 2002-11-11 2004-05-27 Grünenthal GmbH Spirocyclische Cyclohexan-Derivate
US6962459B2 (en) * 2003-08-12 2005-11-08 Sci Products Inc. Crash attenuator with cable and cylinder arrangement for decelerating vehicles
DE102005016460A1 (de) * 2005-04-11 2006-10-19 Grünenthal GmbH Spriocyclische Cyclohexanderivate zur Behandlung von Substanzabhängigkeit
DE102007009235A1 (de) * 2007-02-22 2008-09-18 Grünenthal GmbH Spirocyclische Cyclohexan-Derivate
PT2260042E (pt) * 2008-03-27 2011-12-06 Gruenenthal Gmbh Derivados de ciclo-hexano espirocíclicos substituídos
WO2009118174A1 (fr) * 2008-03-27 2009-10-01 Grünenthal GmbH Cyclohexyldiamines substituées
ATE537143T1 (de) * 2008-03-27 2011-12-15 Gruenenthal Gmbh Spiro(5.5)undecan derivate
CA2719735A1 (fr) 2008-03-27 2009-10-01 Gruenenthal Gmbh Derives substitues du 4-aminocyclohexane
JP5599774B2 (ja) * 2008-03-27 2014-10-01 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング ヒドロキシメチルシクロヘキシルアミン類

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2759000A (en) * 1954-11-12 1956-08-14 Ciba Pharm Prod Inc Certain substituted pyridindoles
FR2455044A1 (fr) * 1979-04-26 1980-11-21 Synthelabo Pyrido-indoles et leur application en therapeutique

Also Published As

Publication number Publication date
FI832829A7 (fi) 1984-02-06
HU187958B (en) 1986-03-28
EP0101574A1 (fr) 1984-02-29
CA1215367A (fr) 1986-12-16
DE3369682D1 (en) 1987-03-12
FI832829A0 (fi) 1983-08-05
US4575508A (en) 1986-03-11
DE3309596A1 (de) 1984-04-05

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